2022
Gene editing reverses arrhythmia susceptibility in humanized PLN-R14del mice: modelling a European cardiomyopathy with global impact
Dave J, Raad N, Mittal N, Zhang L, Fargnoli A, Oh JG, Savoia ME, Hansen J, Fava M, Yin X, Theofilatos K, Ceholski D, Kohlbrenner E, Jeong D, Wills L, Nonnenmacher M, Haghighi K, Costa KD, Turnbull IC, Mayr M, Cai CL, Kranias EG, Akar FG, Hajjar RJ, Stillitano F. Gene editing reverses arrhythmia susceptibility in humanized PLN-R14del mice: modelling a European cardiomyopathy with global impact. Cardiovascular Research 2022, 118: 3140-3150. PMID: 35191471, PMCID: PMC9732517, DOI: 10.1093/cvr/cvac021.Peer-Reviewed Original ResearchConceptsAdeno-associated virus 9Ventricular tachycardiaCardiac functionStroke volumeHigh arrhythmia burdenSustained ventricular tachycardiaSudden cardiac deathCardiac magnetic resonancePre-symptomatic carriersYoung adult miceWeeks of ageDroplet digital polymerase chain reactionArrhythmia burdenVulnerable myocardiumCardiac deathEjection fractionPreclinical evidenceMalignant arrhythmiasVentricular dilationHumanized miceWT miceCardiac outputPolymerase chain reactionPLN-R14DelAdult mice
2018
Intra-tracheal gene delivery of aerosolized SERCA2a to the lung suppresses ventricular arrhythmias in a model of pulmonary arterial hypertension
Strauss B, Sassi Y, Bueno-Beti C, Ilkan Z, Raad N, Cacheux M, Bisserier M, Turnbull IC, Kohlbrenner E, Hajjar RJ, Hadri L, Akar FG. Intra-tracheal gene delivery of aerosolized SERCA2a to the lung suppresses ventricular arrhythmias in a model of pulmonary arterial hypertension. Journal Of Molecular And Cellular Cardiology 2018, 127: 20-30. PMID: 30502350, PMCID: PMC6561115, DOI: 10.1016/j.yjmcc.2018.11.017.Peer-Reviewed Original ResearchMeSH KeywordsAction PotentialsAerosolsAnimalsArrhythmias, CardiacConnexin 43Disease Models, AnimalGene Transfer TechniquesGenetic TherapyHeart Conduction SystemHumansMalePotassium ChannelsPulmonary Arterial HypertensionRats, Sprague-DawleyRNA, MessengerSarcoplasmic Reticulum Calcium-Transporting ATPasesTracheaConceptsPulmonary arterial hypertensionSudden cardiac deathVentricular tachyarrhythmiasCTRL heartsExpression of Cx43Conduction velocityArterial hypertensionHeart rateAP durationAdvanced pulmonary arterial hypertensionIncidence of VTOptical action potential mappingPacing-induced ventricular tachyarrhythmiasRisk of VTAEP substrateElectro-mechanical dysfunctionImpaired chronotropic responseMinimal conduction velocitiesRight ventricular failureSustained ventricular tachyarrhythmiasAPD heterogeneityPulmonary vascular remodelingRapid heart rateAge-matched ratsIntra-tracheal delivery
2017
Increased Afterload Following Myocardial Infarction Promotes Conduction-Dependent Arrhythmias That Are Unmasked by Hypokalemia
Motloch LJ, Ishikawa K, Xie C, Hu J, Aguero J, Fish KM, Hajjar RJ, Akar FG. Increased Afterload Following Myocardial Infarction Promotes Conduction-Dependent Arrhythmias That Are Unmasked by Hypokalemia. JACC Basic To Translational Science 2017, 2: 258-269. PMID: 28798965, PMCID: PMC5547890, DOI: 10.1016/j.jacbts.2017.02.002.Peer-Reviewed Original ResearchAdvanced ischemic heart diseasePost-myocardial infarction patientsIschemic heart diseaseSudden cardiac deathNew large animal modelLarge animal modelMechanisms of arrhythmiasIncreased afterloadResistant hypertensionCardiac deathWorsen outcomesAnterior MIInfarction patientsHeart diseasePathophysiological significanceAnimal modelsElectrophysiological substrateAfterloadHypokalemiaDisease phenotypePatientsArrhythmiasRelevant modelHypertensionMI
2015
Gene therapy to restore electrophysiological function in heart failure
Motloch LJ, Akar FG. Gene therapy to restore electrophysiological function in heart failure. Expert Opinion On Biological Therapy 2015, 15: 803-817. PMID: 25865107, PMCID: PMC5547747, DOI: 10.1517/14712598.2015.1036734.Peer-Reviewed Original ResearchConceptsHeart failureHF patientsMajor public health epidemicPro-arrhythmic activitySafe therapeutic optionSudden cardiac deathCause of morbidityGene therapyPublic health epidemicAbnormal excitabilityCardiac deathTherapeutic optionsTherapeutic effectMyocardial conductionHeart rateLethal arrhythmiasGene therapy approachesElectrophysiological functionUnmet needArrhythmogenic disordersGene-based approachesCalcium cyclingHealth epidemicCardiac gene therapyConduction system
2010
Left ventricular repolarization heterogeneity as an arrhythmic substrate in heart failure.
Akar FG. Left ventricular repolarization heterogeneity as an arrhythmic substrate in heart failure. Minerva Cardioangiologica 2010, 58: 205-12. PMID: 20440250.ChaptersConceptsHeart failureElectrophysiological substrateSudden cardiac deathCalcium handling proteinsRepolarization gradientsVentricular repolarization heterogeneityHeterogeneous remodelingCardiac deathCardiac functionArrhythmic substrateLeft ventriculeHandling proteinsMuscle layerPathophysiological remodelingRepolarization heterogeneityTissue levelsOrgan system levelArrhythmiasGap junctionsIon channelsOverview of mechanismsSub-cellular changesRemodelingFailureVentricule
2009
Mechanoelectrical remodeling and arrhythmias during progression of hypertrophy
Jin H, Chemaly ER, Lee A, Kho C, Hadri L, Hajjar RJ, Akar FG. Mechanoelectrical remodeling and arrhythmias during progression of hypertrophy. The FASEB Journal 2009, 24: 451-463. PMID: 19825979, PMCID: PMC2812033, DOI: 10.1096/fj.09-136622.Peer-Reviewed Original ResearchConceptsConduction delayLeft ventricular mechanical dysfunctionEnd-stage heart failureTissue levelsVentricular mechanical dysfunctionIncidence of arrhythmiasSudden cardiac deathZO-1Pressure overload hypertrophyAction potential prolongationProgression of hypertrophyDisease developmentLV dysfunctionCardiac deathDephosphorylation of Cx43Heart failureAortic bandingElectrical remodelingVentricular tachycardiaMechanical dysfunctionOverload hypertrophyElectrophysiological changesRat modelPotential prolongationProtein ZO-1
2008
Arrhythmia Mechanisms in the Failing Heart
JIN H, LYON AR, AKAR FG. Arrhythmia Mechanisms in the Failing Heart. Pacing And Clinical Electrophysiology 2008, 31: 1048-1056. PMID: 18684263, DOI: 10.1111/j.1540-8159.2008.01134.x.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsHeart failureArrhythmia mechanismsFundamental arrhythmia mechanismsSudden cardiac deathLethal ventricular tachyarrhythmiasCalcium handling proteinsEffective treatment strategiesCardiac deathMalignant arrhythmiasVentricular tachyarrhythmiasElectrical remodelingConduction abnormalitiesFailing HeartTreatment strategiesLethal arrhythmiasElectrophysiological substrateHandling proteinsAction potentialsPatientsArrhythmiasIon channelsDeathHeartTachyarrhythmiasAbnormalities
2006
Mapping arrhythmias in the failing heart: from Langendorff to patient
Akar JG, Akar FG. Mapping arrhythmias in the failing heart: from Langendorff to patient. Journal Of Electrocardiology 2006, 39: s19-s23. PMID: 16920143, DOI: 10.1016/j.jelectrocard.2006.03.011.Peer-Reviewed Educational MaterialsConceptsHeart failureVentricular arrhythmiasOptical action potential mappingSudden cardiac deathCardiac deathIntact tissue preparationsCardiac remodelingMost arrhythmiasArrhythmic substrateArrhythmiasElectrophysiological propertiesMapping arrhythmiasTissue levelsIndividual myocytesMajor causeReentrant excitationOrgan system levelPatientsMultiple mechanismsTissue preparationsHeartRecent findingsHost of changesCellular studiesLangendorff
2002
The Electrophysiological Substrate for Reentry: Unique Insights from High-Resolution Optical Mapping with Voltage-Sensitive Dyes
Rosenbaum D, Akar F. The Electrophysiological Substrate for Reentry: Unique Insights from High-Resolution Optical Mapping with Voltage-Sensitive Dyes. 2002, 568-595. DOI: 10.1201/b14064-18.Peer-Reviewed Original ResearchMajor public health problemReentrant arrhythmiasSudden cardiac deathPublic health problemNormal cardiac rhythmHemodynamic deteriorationCardiac deathVentricular arrhythmiasConduction disturbancesLethal arrhythmiasVoltage-sensitive dyeCardiac rhythmElectrophysiological substrateReentrant circuitMaintenance of reentryArrhythmiasElectrical defibrillationHealth problemsArrhythmia mechanismsMyocardial excitabilityFocal arrhythmiasIntact heartCardiac impulseResolution optical mappingReentrant excitation